Mitochondria are the central regulators of myocardial metabolism and are responsible for maintaining metabolic homeostasis across a wide range of cardiac workloads. The molecular mechanisms that regulate mitochondrial function are gradually being uncovered, but the critical link between mitochondrial morphology and oxidative capacity is unknown. Mitofusin (Mfn) 1 and 2 are two recently-discovered mitochondrial-shaping proteins that are found on the outer membrane and are major regulators of mitochondrial architecture. Recent evidence from our laboratory suggests that cardiac myocyte-specific ablation of both Mfn1 and Mfn2 leads to a greater number of fragmented mitochondria, left ventricular remodeling and systolic dysfunction, and increased mortality during the transition from fetal to post-natal life. Concomitant with changes in mitochondrial and cardiac morphology was decreased expression of nuclear and mitochondrial transcription factors which collectively play a critical role in mitochondrial biogenesis. These findings suggest that mitofusins likely participate in the heart's adaptive metabolic response to increased energetic demand. To address this possibility, we will, for the first time, examine the role of mitofusins in the development of pathological and physiological cardiac hypertrophy and characterize the differential effects of Mfn1 and/or Mfn2 ablation in the adult cardiac myocyte. We will employ an extensive mouse genetic "toolkit" containing mitofusin conditional single and double knockouts, as well as mice with three of four mitofusin alleles deleted (monoallelics). These mice will be used to investigate mitofusins in post-natal cardiac growth and to explore mechanisms by which mitochondrial morphology affects mitochondrial content and respiratory function. These experiments will provide a comprehensive top-down analysis of mitofusin function in the adult mammalian myocardium, linking the intact heart phenotype, isolated cardiac myocyte physiology, and mitochondrial respiration and dynamics.
In the heart, organelles referred to as mitochondria have a critical role in balancing energy production with cellular energetic demand. It is now recognized that mitochondria are dynamic structures that undergo continuous fission and fusion, the latter being regulated by proteins called mitofusins. Using mice with heart- restricted mitofusin deletion, we will examine the importance of these proteins in pathological and physiological cardiac growth and in regulating heart muscle cell physiology.
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